RESUMO
BACKGROUND: Hypopituitarism has been reported in patients with idiopathic normal pressure hydrocephalus (iNPH), which could enhance characteristic symptoms like impaired wakefulness, gait, body balance, and subcortical cognitive deterioration. PURPOSE: To compare basal serum levels of pituitary and sex hormones and serum insulin-like growth factor-1 (S-IGF-1) in patients with iNPH and an age-matched control population, and to correlate the preoperative hormone levels with symptoms and signs pre-operatively and three months after surgery. METHODS: A cross-sectional case control design was used. Patients diagnosed with iNPH, n=108 (65 men and 43 women, mean age 72.3 years), were consecutively included during 2006-2011 at Sahlgrenska University Hospital, Gothenburg, Sweden. S-TSH, S-free T4, S-FSH, S-LH, S-prolactin, plasma ACTH, S-testosterone, S-oestradiol and S-IGF-1 were examined. Symptoms and signs were scored using the iNPH scale score. Population controls, n=146, were recruited from the WHO MONICA project, Gothenburg in 2008. RESULTS: Men and women with iNPH had higher S-IGF-1 than controls (p<0.001). Women with iNPH had lower S-TSH (p=0.016) than controls, but the frequency of levothyroxine substitution was similar. Among men, a higher level of S-IGF-1 was associated with milder symptoms, while higher levels of S-FSH and S-LH were associated with more severe symptoms. CONCLUSIONS: Patients with iNPH did not have lower levels of pituitary or sex hormones but presented with higher levels of S-IGF-1, compared with healthy, age-matched controls. Higher S-IGF-1 in men was related to milder mental and physical symptoms and signs.
Assuntos
Hidrocefalia de Pressão Normal/sangue , Hipopituitarismo/sangue , Fator de Crescimento Insulin-Like I/metabolismo , Hormônio Adrenocorticotrópico/sangue , Adulto , Estudos de Casos e Controles , Estudos Transversais , Estradiol/sangue , Feminino , Hormônio Foliculoestimulante/sangue , Humanos , Hormônio Luteinizante/sangue , Masculino , Pessoa de Meia-Idade , Prolactina/sangue , Testosterona/sangue , Tireotropina/sangue , Tiroxina/sangueRESUMO
GH may exert direct growth-promoting and metabolic actions on target tissues, but most of its effects are mediated by circulating (endocrine) or local (auto-/paracrine) IGF-I. The GH/IGF-I system has an important role in cardiac development and in maintaining the structure and function of the heart. A subgroup of children with pronounced heart defects will eventually need transplants, owing to congestive heart failure. Since the symptoms are often severe and may progress while waiting for surgery, it is necessary to develop supportive medical treatment. GH has been proposed as a therapeutic agent in adults with heart failure, but to date studies are lacking on children and more information is necessary. We have examined the expression of IGF-I mRNA and GH-receptor (GH-R) mRNA in children undergoing surgery for congenital heart disease. Eighteen children scheduled for open-heart surgery were included in the study. Right auricular biopsies were taken at the time of venous catheterization preceding cardiac bypass. The specimens were analysed using realtime PCR. We were able to show expression of both IGF-I mRNA and GH-R mRNA in the pediatric heart. The relative expressions were intercorrelated (r=0.75, p<0.001). GH-R mRNA correlated positively to standardized weight (r=0.65, p=0.004), body mass index (BMI) (r=0.59, p=0.01), and standardized BMI (r=0.59, p=0.01). IGF-I mRNA only correlated to BMI (r=0.50, p=0.04). This is the first study displaying cardiac expression of IGF-I mRNA and GH-R mRNA in children with congenital heart disease, although further studies are needed to define a role for GH in the treatment of these patients.
Assuntos
Expressão Gênica , Cardiopatias Congênitas/metabolismo , Fator de Crescimento Insulin-Like I/genética , Miocárdio/química , RNA Mensageiro/análise , Receptores da Somatotropina/genética , Adolescente , Biópsia , Índice de Massa Corporal , Pré-Escolar , Feminino , Hormônio do Crescimento/uso terapêutico , Cardiopatias Congênitas/cirurgia , Humanos , Lactente , Recém-Nascido , Masculino , Reação em Cadeia da PolimeraseRESUMO
Apart from regulating somatic growth and metabolism, evidence suggest that the GH/ IGF-I axis is involved in the regulation of brain growth, development and myelination. Moreover, growth hormone (GH) and particularly IGF-I have been attributed neuroprotective effects in different in vitro and in vivo experimental models. In addition, both GH and IGF-I affect cognition and biochemistry in the adult brain. Some of the effects of GH are suggested to be mediated by circulating IGF-I, while other effects may be due to locally produced IGF-I within the brain. It is also possible that GH may act directly on the central nervous system (CNS) without involving IGF-I (either circulating or locally). Plasticity in the CNS may be viewed as changes in the functional interplay between the major cell types neurons, astrocytes and oligodendrocytes. GH and IGF-I affect all these cell types in several aspects. Apart from neuroprotective effects of GH and IGF-I in different experimental models of CNS injury, IGF-I has been found to increase progenitor cell proliferation and new neurons, oligodendrocytes, and blood vessels in the dentate gyrus of the hippocampus. In the adult cerebral cortex, it appears that only oligodendrogenesis is affected. The increase of IGF-I on endothelial cell phenotype may explain the increase in cerebral arteriole density observed after GH treatment. In the present review, different aspects of the GH/IGF-I axis effects on the brain will be discussed with particular emphasis on neuroprotection, regeneration and brain plasticity. Moreover, recent findings describing neuroprotective effects and effects on synaptic plasticity by GH secretagogues will be reviewed.
Assuntos
Encéfalo/metabolismo , Hormônio do Crescimento Humano/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Regeneração Nervosa/fisiologia , Fármacos Neuroprotetores/metabolismo , Animais , Barreira Hematoencefálica/metabolismo , Cognição/efeitos dos fármacos , Cognição/fisiologia , Hormônio do Crescimento Humano/farmacologia , Humanos , Fator de Crescimento Insulin-Like I/farmacologia , Redes e Vias Metabólicas/fisiologia , Fármacos Neuroprotetores/farmacologia , Receptores da Somatotropina/fisiologiaRESUMO
To study the role of the growth hormone receptor (GHR) in the development of cardiovascular structure and function, female GHR gene-disrupted or knockout (KO) and wild-type (WT) mice at age 18 wk were used. GHR KO mice had lower plasma renin levels (12 +/- 2 vs. 20 +/- 4 mGU/ml, P < 0.05) and increased aortic endothelial NO synthase (eNOS) expression (146%, P < 0.05) accompanied by a 25% reduction in systolic blood pressure (BP, 110 +/- 4 vs. 147 +/- 3 mmHg, P < 0.001) compared with WT mice. Aldosterone levels were unchanged, whereas the plasma potassium concentration was elevated by 14% (P < 0.05) in GHR KO. Relative left ventricular weight was 14% lower in GHR KO mice (P < 0.05), and cardiac dimensions as analyzed by echocardiography were similarly reduced. Myograph studies revealed a reduced maximum contractile response in the aorta to norepinephrine (NE) and K(+) (P < 0.05), and aorta media thickness was decreased in GHR KO (P < 0.05). However, contractile force was normal in mesenteric arteries, whereas sensitivity to NE was increased (P < 0.05). Maximal acetylcholine-mediated dilatation was similar in WT and GHR KO mice, whereas the aorta of GHR KO mice showed an increased sensitivity to acetylcholine (P < 0.05). In conclusion, loss of GHR leads to low BP and decreased levels of renin in plasma as well as increase in aortic eNOS expression. Furthermore, GHR deficiency causes functional and morphological changes in both heart and vasculature that are beyond the observed alterations in body size. These data suggest an important role for an intact GH/IGF-I axis in the maintenance of a normal cardiovascular system.
Assuntos
Pressão Sanguínea/fisiologia , Sistema Cardiovascular/metabolismo , Óxido Nítrico Sintase Tipo II/biossíntese , Receptores da Somatotropina/deficiência , Renina/sangue , Aldosterona/sangue , Animais , Aorta Torácica/enzimologia , Aorta Torácica/metabolismo , Fenômenos Fisiológicos Cardiovasculares , Ecocardiografia Doppler , Eletrocardiografia , Feminino , Coração/anatomia & histologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Contração Muscular/fisiologia , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo III , Tamanho do Órgão , Potássio/sangue , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
Although initially recognised for their GH-releasing properties, the cardiovascular system has been recognised as a potentially important target for GH secretagogues (GHS). Moreover, a limited number of studies also indicate cardiovascular effects of ghrelin. So far reported cardiovascular effects of GHS and/or ghrelin include lowering of peripheral resistance, possible improvement of contractility and cardioprotective effects both in vivo and in vitro. Taken together, these results offer an interesting perspective on the future where further studies aiming at evaluating a role of GHS and ghrelin in the treatment of cardiovascular disease are warranted.
Assuntos
Sistema Cardiovascular/metabolismo , Hormônio do Crescimento/metabolismo , Hormônios Peptídicos/farmacologia , Hormônios Peptídicos/fisiologia , Animais , Apoptose/efeitos dos fármacos , Grelina , Hormônio do Crescimento/uso terapêutico , Humanos , Isquemia Miocárdica/prevenção & controle , Miócitos Cardíacos/citologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/fisiologia , Vasodilatação/fisiologiaRESUMO
In this review, the great importance of growth hormone (GH) for the maintenance of cardiac function in adult life is discussed. Physiological effects of GH are discussed as well as the cardiac dysfunction caused both by GH excess (acromegaly) and by GH deficiency in adult hypopituitary patients. In both acromegaly and adult GH deficiency, there is also increased cardiovascular morbidity and mortality. Finally, the effect of GH treatment in heart failure is discussed.
Assuntos
Hormônio do Crescimento/fisiologia , Coração/fisiologia , Miocárdio/metabolismo , Acromegalia/fisiopatologia , Animais , Débito Cardíaco/fisiologia , Hormônio do Crescimento/biossíntese , Hormônio do Crescimento/deficiência , Hormônio do Crescimento/uso terapêutico , Coração/fisiopatologia , Cardiopatias/tratamento farmacológico , Cardiopatias/fisiopatologia , Humanos , Hipopituitarismo/fisiopatologia , Fator de Crescimento Insulin-Like I/fisiologia , Resultado do TratamentoRESUMO
Clinical studies in patients with acromegaly have shown that growth hormone (GH) exerts both short- and long-term effects on the structure and function of the heart. Moreover, chronic growth hormone deficiency (GHD) has been associated with impaired cardiac performance, low heart rate and impaired left ventricular systolic function. Exercise capacity in patients with GHD is significantly reduced and in some severely affected individuals, dilated cardiomyopathy and heart failure has been reported. GHD has also been associated with a number of risk factors for cardiovascular disease. Altered lipoprotein metabolism and elevated fibrinogen and plasminogen activator inhibitor-1 activity are associated with GHD, and the risk of hypertension is increased in GH-deficient men. Subcutaneous and intra-abdominal fat mass have also been found to be abnormally high in these patients. These effects may contribute to an increased risk of death from cardiovascular disease. GH is therefore an important factor in the development and function of the cardiovascular system. In this paper, the effects of GH on the physiological mechanisms of the cardiovascular system are discussed, including the effect of GHD on cardiovascular disease risk. We will also discuss the effects of long-term GH replacement therapy in this patient population.
Assuntos
Doenças Cardiovasculares/etiologia , Hormônio do Crescimento/uso terapêutico , Terapia de Reposição Hormonal , Hormônio do Crescimento Humano/metabolismo , Erros Inatos do Metabolismo de Esteroides/complicações , Erros Inatos do Metabolismo de Esteroides/tratamento farmacológico , Animais , Hormônio do Crescimento/efeitos adversos , Coração/efeitos dos fármacos , Terapia de Reposição Hormonal/efeitos adversos , Hormônio do Crescimento Humano/deficiência , Humanos , Hipertrofia Ventricular Esquerda/induzido quimicamente , Contração Miocárdica/efeitos dos fármacos , Fatores de Risco , Resistência Vascular/efeitos dos fármacosRESUMO
Recent experimental data demonstrate cardiovascular effects of the GH secretagogues (GHSs) hexarelin and ghrelin, the proposed natural ligand for the GHS receptor. Moreover, specific cardiac binding sites for GHSs have been suggested. The aim of the present study was to investigate if the natural ligand ghrelin and synthetic GHS peptide hexarelin and analogues have direct effects on the cardiomyocyte cell line, H9c2. Hexarelin stimulated thymidine incorporation in a dose-dependent manner with significant responses at 3 micro M (147+/-3% of control, P<0.01) and elicited maximal effects at concentrations around 30 micro M. This activity was seen already after 12 h of incubation with a maximal effect after 18 h (176+/-9% of control, P<0.01). Ghrelin also had a significant stimulatory effect on thymidine incorporation (129+/-2% of control at 3 micro M and 18 h, P<0.05). The stimulatory effect on thymidine incorporation of hexarelin, Tyr-Ala-hexarelin, EP80317 and ghrelin was specific and no stimulatory effect was observed with the truncated GH-releasing peptide EP51389 or the non-peptidyl GHS MK-0677. In competitive binding studies, (125)I-labeled Tyr-Ala-hexarelin was used as radioligand and competition curves showed displacement with hexarelin, Tyr-Ala-hexarelin, EP80317 and ghrelin, whereas MK-0677 and EP51389 produced very little displacement at 1 micro M concentration, adding further support for an alternative subtype binding site in the heart compared with the pituitary. In conclusion, we have demonstrated a dose-dependent and specific stimulation of cardiomyocyte thymidine incorporation by natural and synthetic GHS analogues, suggesting increased cell proliferation and binding of GHS to H9c2 cardiomyocyte cell membranes. These findings support potential peripheral effects of GHS on the cardiovascular system independent of an increased GH secretion.
Assuntos
Miócitos Cardíacos/efeitos dos fármacos , Oligopeptídeos/farmacologia , Hormônios Peptídicos/farmacologia , Ligação Competitiva , Divisão Celular/efeitos dos fármacos , Linhagem Celular , Relação Dose-Resposta a Droga , Grelina , Hormônio do Crescimento/metabolismo , Humanos , Ligação Proteica , Estimulação QuímicaRESUMO
BACKGROUND AND OBJECTIVE: Beta-adrenoreceptor blocking agents are important for the treatment of myocardial infarction (MI). Accumulating evidence also indicates that growth hormone (GH) improves cardiac function after MI in rats. We aimed to investigate the cardiovascular effects of combined treatment in an animal model of MI. METHODS: MI was induced in rats by ligation of the left coronary artery. Three days after MI, animals were randomly assigned to one of four groups: controls (C) (n=19); GH (n=19) receiving s.c. 2 mg/kg per day rhGH; metoprolol (M) group (n=19) receiving 24 mg/kg per day and combined group (GHM) (n=20) treated with both GH (2 mg/kg per day s.c.) and M (24 mg/kg per day) for 9 days. Transthoracic echocardiography was performed before and after treatment. RESULTS: Serum levels of insulin-like growth factor I were significantly elevated in the GH-group but not in the GHM group compared to controls. Left ventricular volumes, cardiac index, systolic blood pressure, were similar in all groups. Percent changes in ejection fraction compared to baseline were; GH (6.1+/-5.0%) and GHM (6.1+/-4.2%) vs. C (-12.5+/-3.0%), P<0.01, M (-7.3+/-4.2%). The occurrence of aneurysms was not significantly different between the various treatment regimes. CONCLUSION: Treatment with growth hormone alone or in combination with metoprolol preserved left ventricular function after MI.
Assuntos
Antagonistas Adrenérgicos beta/uso terapêutico , Hormônio do Crescimento/uso terapêutico , Coração/fisiologia , Metoprolol/uso terapêutico , Infarto do Miocárdio/tratamento farmacológico , Aneurisma/complicações , Aneurisma/tratamento farmacológico , Animais , Peso Corporal , Quimioterapia Combinada , Ecocardiografia , Hemodinâmica/efeitos dos fármacos , Hemodinâmica/fisiologia , Fator de Crescimento Insulin-Like I/efeitos dos fármacos , Masculino , Modelos Cardiovasculares , Infarto do Miocárdio/complicações , Infarto do Miocárdio/fisiopatologia , Ratos , Ratos Sprague-Dawley , Volume Sistólico/efeitos dos fármacos , Volume Sistólico/fisiologia , Fatores de Tempo , Resultado do Tratamento , Função Ventricular Esquerda/efeitos dos fármacos , Função Ventricular Esquerda/fisiologiaRESUMO
Accumulating data show that growth hormone (GH) and insulin-like growth factor-I (IGF-I) have major effects on the cardiovascular system. In the present study we have directly compared GH and IGF-I in an in vivo rat model of experimental myocardial infarction. Four weeks after ligation of the left coronary artery, male rats were treated with recombinant human (rh) GH 1.1 mg/kg per day, rhIGF-I 3.0 mg/kg per day or saline s.c. for 2 weeks. Transthoracic echocardiography was performed before and after the treatment period. Both GH and IGF-I reduced total peripheral resistance (P< 0.01), end-systolic wall stress (P< 0.01) and end-systolic short-axis area (P< 0.001 and P< 0.05). GH also increased area fractional shortening (P< 0.05). Stroke volume (SV) and SV index were improved by IGF-I (P< 0.0001), and SV tended to be increased by GH (P= 0.12). In conclusion, GH and IGF-I had similar beneficial effects on systolic function and peripheral resistance after experimental myocardial infarction.
Assuntos
Hormônio do Crescimento Humano/farmacologia , Fator de Crescimento Insulin-Like I/farmacologia , Infarto do Miocárdio/tratamento farmacológico , Animais , Peso Corporal/efeitos dos fármacos , Modelos Animais de Doenças , Ecocardiografia Doppler , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/patologia , Insuficiência Cardíaca/fisiopatologia , Humanos , Fator de Crescimento Insulin-Like I/genética , Fator de Crescimento Insulin-Like I/metabolismo , Masculino , Infarto do Miocárdio/patologia , Infarto do Miocárdio/fisiopatologia , Miocárdio/metabolismo , Miocárdio/patologia , Tamanho do Órgão/efeitos dos fármacos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Proteínas Recombinantes/farmacologia , Volume Sistólico/efeitos dos fármacos , Sístole/efeitos dos fármacos , Resistência Vascular/efeitos dos fármacosRESUMO
The aims of this study were to examine, in vivo, the effects of GH treatment on myocardial energy metabolism, function, morphology, and neurohormonal status in rats during the early postinfarct remodeling phase. Myocardial infarction (MI) was induced in male Sprague Dawley rats. Three different groups were studied: MI rats treated with saline (n = 7), MI rats treated with GH (MI + GH; n = 11; 3 mg/kg x day), and sham-operated rats (sham; n = 8). All rats were investigated with 31P magnetic resonance spectroscopy and echocardiography at 3 days after MI and 3 weeks later. After 3 weeks treatment with GH, the phosphocreatine/ATP ratio increased significantly, compared with the control group (MI = 1.69 +/- 0.09 vs. MI + GH = 2.42 +/- 0.05, P < 0.001; sham = 2.34 +/- 0.08). Treatment with GH significantly attenuated an increase in left ventricular end systolic volume and end diastolic volume. A decrease in ejection fraction was prevented in GH-treated rats (P < 0.05 vs. MI). Myocardial and plasma noradrenaline levels were significantly lower in MI rats treated with GH. These effects were accompanied by normalization of plasma brain natriuretic peptide levels (sham = 124.1 +/- 8.4; MI = 203.9 +/- 34.7; MI + GH = 118.3 +/- 8.4 ng/ml; P < 0.05 vs. MI). In conclusion, GH improves myocardial energy reserve, preserves left ventricular function, and attenuates pathologic postinfarct remodeling in the absence of induction of left ventricular hypertrophy in postinfarct rats. The marked decrease in myocardial content of noradrenaline, after GH treatment, may protect myocardium from adverse effects of catecholamines during postinfarct remodeling.
Assuntos
Catecolaminas/metabolismo , Metabolismo Energético , Hormônio do Crescimento Humano/uso terapêutico , Infarto do Miocárdio/tratamento farmacológico , Miocárdio/metabolismo , Animais , Peso Corporal , Dopamina/análise , Dopamina/sangue , Ecocardiografia Doppler , Epinefrina/análise , Epinefrina/sangue , Hemodinâmica , Hormônio do Crescimento Humano/sangue , Fator de Crescimento Insulin-Like I/análise , Masculino , Infarto do Miocárdio/metabolismo , Miocárdio/química , Peptídeo Natriurético Encefálico/sangue , Ratos , Ratos Sprague-Dawley , Receptores Adrenérgicos beta/análise , Função Ventricular EsquerdaRESUMO
Brief coronary occlusion followed by reperfusion leads to reversible myocardial dysfunction (stunning) which can induce irreversible damage of other organ systems. We studied the effects of pretreatment with recombinant human GH (rhGH) and the GH-secretagogue GHRP-2 on myocardial stunning in a blood-perfused isolated rabbit heart model. In a first set of experiments, effects of bolus rhGH administration (3.5 mg/kg) (n = 5) into the aortic root of unpretreated animals were compared with those of saline (n = 6). In a second set, animals were pretreated for 14 days with SC rhGH 3.5 mg/kg x day (n = 9) or 160 microg/kg x day GHRP-2 (n = 8) in two divided doses. Body weight and plasma concentrations of rhGH, rabbit GH (rGH) and IGF-I were determined before and at the end of 14 days pretreatment. Hearts were excised and submitted to 15 min ischemia followed by 80 min reperfusion, after which postischemic recovery was compared with nonischemic hearts mounted into the same system. At study end, all hearts were snap-frozen to examine markers of apoptosis. Circulating levels of rabbit GH (rGH) remained identical in all animals. Pretreatment with rhGH for 14 days induced a 142 +/- 116% rise of serum IGF-I vs. 8 +/- 15% with GHRP-2 (P < 0.001) and increased body weight with 6.8 +/- 2.5% vs. 3.4 +/- 3.3% with GHRP-2 (P = 0.01). A bolus injection of rhGH did not alter myocardial function compared with saline allowing data from these experiments to be pooled into one ischemic control group for further analysis of the effect of pretreatment. No difference in postischemic recovery of left ventricular systolic function among the unpretreated, rhGH pretreated and GHRP-2 pretreated hearts was apparent. At the end of reperfusion, a 3-fold higher end-diastolic pressure (EDP) persisted in the unpretreated and rhGH pretreated hearts compared with the nonischemic hearts. In the GHRP-2 pretreated hearts, EDP decreased to half the pressure observed in unpretreated and rhGH pretreated hearts (all P < or = 0.02), a level which was indistinguishable from that in the non-ischemic hearts, suggesting full postischemic recovery of diastolic function. There were no signs of increased apoptosis in the experimental groups. In conclusion, 14 days pretreatment with GHRP-2, but not rhGH, protected selectively against the diastolic dysfunction of myocardial stunning in this model. This observation may open perspectives for GH-secretagogues as cardioprotective agents.
Assuntos
Diástole , Modelos Animais de Doenças , Hormônio do Crescimento Humano/farmacologia , Miocárdio Atordoado/fisiopatologia , Oligopeptídeos/farmacologia , Animais , Apoptose/efeitos dos fármacos , Pressão Sanguínea , Peso Corporal , Circulação Coronária , Hormônio do Crescimento/sangue , Humanos , Fator de Crescimento Insulin-Like I/metabolismo , Coelhos , Sístole , Função Ventricular EsquerdaRESUMO
The present study evaluated the ability of insulin-like growth factor I (IGF-I) complexed with IGF binding protein-3 (IGFBP-3) to modulate the sepsis-induced inhibition of protein synthesis in gastrocnemius. Beginning 16 h after the induction of sepsis, either the binary complex or saline was injected twice daily via a tail vein, with measurements made 3 and 5 days later. By day 3, sepsis had reduced plasma IGF-I concentrations approximately 50% in saline-treated rats. Administration of the binary complex provided exogenous IGF-I to compensate for the sepsis-induced diminished plasma IGF-I. Sepsis decreased rates of protein synthesis in gastrocnemius relative to controls by limiting translational efficiency. Treatment of septic rats with the binary complex for 5 days attenuated the sepsis-induced inhibition of protein synthesis and restored translational efficiency to control values. Assessment of potential mechanisms regulating translational efficiency showed that neither the sepsis-induced change in gastrocnemius content of eukaryotic initiation factor 2B (eIF2B), the amount of eIF4E associated with 4E binding protein-1 (4E-BP1), nor the phosphorylation state of 4E-BP1 or eIF4E were altered by the binary complex. Overall, the results are consistent with the hypothesis that decreases in plasma IGF-I are partially responsible for enhanced muscle catabolism during sepsis.
Assuntos
Proteínas de Transporte , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Proteínas Musculares/biossíntese , Músculo Esquelético/metabolismo , Sepse/metabolismo , Animais , Glicemia/metabolismo , Fator de Iniciação 2B em Eucariotos/metabolismo , Fator de Iniciação 4E em Eucariotos , Insulina/sangue , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/farmacologia , Fator de Crescimento Insulin-Like I/genética , Fator de Crescimento Insulin-Like I/farmacologia , Peptídeos e Proteínas de Sinalização Intracelular , Fígado/metabolismo , Masculino , Músculo Esquelético/anatomia & histologia , Músculo Esquelético/efeitos dos fármacos , Tamanho do Órgão , Fatores de Iniciação de Peptídeos/metabolismo , Fosfoproteínas/metabolismo , Biossíntese de Proteínas , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Receptor IGF Tipo 1/genética , Receptores da Somatotropina/genéticaRESUMO
BACKGROUND: Protein synthesis in skeletal muscle is reduced following starvation and restored by feeding. The mediators and mechanisms are incompletely understood. The aim of this study was to evaluate whether prolongation of undernutrition induced changes in muscle gene expression at the level of mRNA and protein. MATERIALS AND METHODS: The changes in myosin heavy-chain 2X mRNA in adult partially starved (50% of ad libitum standard rodent chow intake for 4 or 7 days) C57BL mice or subsequently refed mice were studied. Ad libitum-fed mice were used as controls. Protein synthesis, total RNA and myosin heavy-chain 2X mRNA concentrations were determined. Plasma concentrations of amino acids were measured by high-performance liquid chromatography. RESULTS: Partial starvation of 4 and 7 days reduced bodyweight by 15.6 +/- 1% and 17.1 +/- 2.1% (P < or = 0.05) vs. ad libitum fed controls. Protein synthesis was reduced by 32 +/- 9% and protein content by 20 +/- 4% (P < or = 0.05) following 7 days of partial starvation. Plasma amino acid concentrations were increased (6297 +/- 853) in refed animals vs. ad libitum-fed controls (3057 +/- 141, P < or = 0.05). Total RNA concentration (micrograms RNA micrograms(-1) DNA) in skeletal muscle was unchanged. Myosin heavy-chain 2X mRNA concentration did not change following 4 days of partial starvation but increased by 24 +/- 5% (P < or = 0.05) following 7 days of partial starvation, hence suggesting that expression of myosin mRNA was nutritionally altered. CONCLUSION: Postprandial stimulation of protein synthesis following starvation may thus be a combination of increased mRNA availability and increased translation. This effect may be activated by peak concentrations of amino acids in plasma following feeding.
Assuntos
Proteínas Musculares/genética , Músculo Esquelético/metabolismo , Miofibrilas/metabolismo , RNA Mensageiro/metabolismo , Inanição/metabolismo , Aminoácidos/sangue , Animais , Glicemia/análise , Peso Corporal , Isótopos de Carbono/metabolismo , Feminino , Alimentos , Insulina/sangue , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Musculares/metabolismo , Miofibrilas/genética , Miosinas/genética , Fenilalanina/metabolismoRESUMO
Cardiovascular abnormalities represent the major cause of death in patients with acromegaly. We evaluated cardiac structure, function, and energy status in adult transgenic mice overexpressing bovine GH (bGH) gene. Female transgenic mice expressing bGH gene (n = 11) 8 months old and aged matched controls (n = 11) were used. They were studied with two-dimensional guided M-mode and Doppler echocardiography. The animals (n = 6) for each group were examined with 31P magnetic resonance spectroscopy to determine the cardiac energy status. Transgenic mice had a significantly higher body weight (BW), 53.2+/-2.4 vs. 34.6+/-3.7 g (P < 0.0001) and hypertrophy of left ventricle (LV) compared with normal controls: LV mass/BW 5.6+/-1.6 vs. 2.7+/-0.2 mg/g, P < 0.01. Several indexes of systolic function were depressed in transgenic animals compared with controls mice such as shortening fraction 25+/-3.0% vs. 39.9+/-3.1%; ejection fraction, 57+/-9 vs. 77+/-5; mean velocity of circumferential shortening, 4.5+/-0.8 vs. 7.0+/-1.1 circ/sec, p < 0.01. Creatine phosphate-to-ATP ratio was significantly lower in bGH overexpressing mice (1.3+/-0.08 vs. 2.1+/-0.23 in controls, P < 0.05). Ultrastructural examination of the hearts from transgenic mice revealed substantial changes of mitochondria. This study provides new insight into possible mechanisms behind the deteriorating effects of long exposure to high level of GH on heart function.
Assuntos
Metabolismo Energético , Expressão Gênica , Hormônio do Crescimento/genética , Cardiopatias/etiologia , Acromegalia/complicações , Trifosfato de Adenosina/metabolismo , Animais , Peso Corporal , Bovinos , Ecocardiografia , Feminino , Hormônio do Crescimento/fisiologia , Cardiopatias/patologia , Cardiopatias/fisiopatologia , Hipertrofia Ventricular Esquerda/etiologia , Hipertrofia Ventricular Esquerda/patologia , Hipertrofia Ventricular Esquerda/fisiopatologia , Espectroscopia de Ressonância Magnética , Camundongos , Camundongos Transgênicos , Miocárdio/metabolismo , Miocárdio/patologia , Tamanho do Órgão , Fosfocreatina/metabolismo , SístoleRESUMO
Recent advances in transgenic technology have made the mouse a particularly interesting small animal in cardiovascular research. Increasingly sophisticated experimental methods and tools are needed for detailed characterization of cardiovascular physiology and biochemistry in the mice. The objective of this study was to develop a method for noninvasive evaluation of cardiac energy metabolism in the mouse. Cardiac gated (31)P magnetic resonance spectroscopy using Image Selected in Vivo Spectroscopy (ISIS) method was applied in old mice overexpressing bovine growth hormone (bGH) (n = 5) and control mice (n = 5). The localized volumes of interest were 128 and 112 microL, respectively. Phosphocreatine-to-ATP ratio was 1.5 +/- 0.13 in the bGH mice and 2.1 +/- 0.04 in the control group (P < 0.01). The study demonstrates the feasibility of application of volume-selective (31)P MRS for evaluation of cardiac energy metabolism in the mouse under maintained physiological conditions.
Assuntos
Metabolismo Energético , Hormônio do Crescimento/metabolismo , Coração/fisiologia , Imageamento por Ressonância Magnética/instrumentação , Imageamento por Ressonância Magnética/métodos , Camundongos Transgênicos , Animais , Bovinos , Coração/diagnóstico por imagem , Camundongos , Isótopos de Fósforo , Radiografia , Análise Espectral/métodosRESUMO
Feeding stimulates protein synthesis in skeletal muscles, although the regulatory mechanisms are incompletely understood. The aim of this study was to determine whether this could be detected at the gene transcription level for postprandial stimulation of the synthesis of muscle proteins. Healthy male volunteers were investigated after an overnight fast. Open muscle biopsies were performed in the starved state and 3 h after meal intake, consisting of 0.15 gN/kg, 12 kcal/kg. Blood samples were drawn every 15 to 30 min for 5 h. Myosin mRNA and insulin growth factor-I (IGF-I) mRNA were measured by solution hybridization assay in homogenized muscle specimens. After food intake, plasma glucose concentrations increased from 5.0 +/- 0.1 to 7.3 +/- 0.3 (P < or = 0.001), and insulin concentration rose from 3.8 +/- 0.5 mU/L before to 75.3 +/- 11.4 15 min after the meal (P < or = 0.001). Plasma concentration of free fatty acids declined after food intake (P < or = 0.001). Plasma concentrations of amino acids increased from basal values (2864 +/- 128 microM) to 4419 +/- 262 microM (P < or = 0.05) 90 min after meal ingestion. Myosin mRNA concentration in the biopsied muscle tissue was higher during starvation and was reduced by 20% after food intake: 10.8 +/- 1.3 amol mRNA/microgram DNA in the starved state and 8.5 +/- 1.3 amol mRNA/microgram DNA after food intake (P < or = 0.05). Feeding did not alter IGF-I mRNA concentrations in muscle: 0.51 +/- 0.05 and 0.55 +/- 0.06 amol/microgram DNA in the starved and fed state, respectively (P < or = 0.48). Improved protein balance by stimulation of protein synthesis has been related to increased plasma amino acids. Interestingly, in the short term, this was not related to increases in gene transcription of either myofibrillar proteins (myosin) or muscle IGF-I. Thus, postprandial stimulation of protein synthesis appears not to be regulated by increased gene transcription but by increased translation using the increased concentrations of amino acids. In contrast, as far as the 2X myosin mRNA level is concerned, this is enhanced during starvation, which facilitates rapid recovery once the availability of substrate is resumed.
Assuntos
Alimentos , Regulação da Expressão Gênica , Músculo Esquelético/metabolismo , Miosinas/biossíntese , Biossíntese de Proteínas , Transcrição Gênica , Adulto , Aminoácidos/sangue , Glicemia/metabolismo , Ácidos Graxos não Esterificados/sangue , Humanos , Insulina/sangue , Fator de Crescimento Insulin-Like I/biossíntese , Fator de Crescimento Insulin-Like I/genética , Cinética , Masculino , Miosinas/genética , RNA Mensageiro/análiseRESUMO
Several studies have shown that GH can enhance cardiac performance in rats after experimental myocardial infarction and in humans with congestive heart failure. In the present study, the hemodynamic effects of hexarelin (Hex), an analog of GH-releasing peptide-6 and a potent GH secretagogue, were compared with the effects of GH. Four weeks after ligation of the left coronary artery male rats were treated sc twice daily with hexarelin [10 microg/kg x day (Hex10) or 100 microg/kg x day (Hex100)], recombinant human GH (2.5 mg/kg x day), or 0.9% NaCl for 2 weeks. Transthoracic echocardiography was performed before and after the treatment period. GH, but not Hex, increased body weight gain. GH and Hex100 decreased total peripheral resistance (P < 0.05) and increased stroke volume (P < 0.05 and P < 0.01, respectively) and stroke volume index (P = 0.06 and P < 0.01, respectively) vs. NaCl. Cardiac output was increased by GH and Hex100 (P < 0.05), and cardiac index was increased by Hex100 with a borderline significance for GH (P = 0.06). In conclusion, Hex improves cardiac function and decreases peripheral resistance to a similar extent as exogenous GH in rats postmyocardial infarction. The mechanisms of these effects are unclear; they could be mediated by GH or a direct effect of Hex on the cardiovascular system.